Plans describe the continuation of an ambitious and highly successful program investigating the fundamental chemical behavior of recently discovered, biologically-active marine metabolites. The research plan details innovative solutions to the most challenging aspects presented by these unique natural products. Studies will advance basic synthesis methodology for stereocontrolled strategies toward highly functionalized target molecules. The program is organized in two categories. I. Macrolide Anti-tumor Antibiotics Part A: Plans for synthesis of amphidinolide P are presented. The amphidinolides are among the most potent anti-tumor agents discovered, with remarkable activity in nearly all NCI tumor cell lines. Extremely limited quantities have hampered biological research. The proposed chemistry will develop functionalized amphidinolide P. Part B. Efforts for synthesis of leucascandrolide A are presented. The recently discovered macrolide displays powerful anti- tumor and anti-fungal properties, and inhibits Candida albicans, an opportunistic yeast infection of many immunocompromised patients. Allylstannane methodology will offer innovative solutions for rapid construction of the alternating 1, 3, 5...oxygenation pattern. Efficient stereoselective syntheses of substituted tetrahydropyran rings, as bridging elements of this antibiotic will be addressed. II. Marine Diterpenes. Part A. Studies of the novel, nine-membered xenicanes are focused on the synthesis of 4-hydroxydictyolactone, a representative structure with anti-tumor and anti-bacterial activity. Investigations of intramolecules alpha-sulfonyl carbanion condensations with omega-aldehydes will provide for assembly of the rigid ring system. Studies of the three contiguous stereocenters (stereotriad) as presented in the xenicanes. Part B. Synthesis of the eleven-membered dolabellane diterpene 4,5-deoxyneodolabelline, will document two strategies for stereocontrolled formation of [9.3.0] cyclotetradecanes. Investigations will highlight previous discoveries for alpha-sulfonyl carbanion chemistry, used to trigger a transannular oxidative ring closure of the bridging pyran. Palladium-catalyzed macrocyclization offers an innovative strategy for stereocontrolled ring formation. A particularly rich spectrum of biological activity, including important anti-tumor activity, is exhibited throughout this class of novel medium-ring metabolites.